tbuckley/cabot-search huggingface dataset:
A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota
Authors: Zhanzhan Li, Bing Zhang, Ning Wang, Zhenqiang Zuo, Hong Wei, Fangqing Zhao
Journal: Gut (2022)

Objective The obesity epidemic and its metabolic complications continue to be a major global public health threat with limited effective treatments, especially drugs that can be taken orally. Peptides are a promising class of molecules that have gained increased interest for their applications in medicine and biotechnology. In this study, we focused on looking for peptides that can be administrated orally to treat obesity and exploring its mechanisms. Design Here, a 9-amino-acid peptide named D3 was designed and administered orally to germ-free (GF) mice and wild-type (WT) mice, rats and macaques. The effects of D3 on body weight and other basal metabolic parameters were evaluated. The effects of D3 on gut microbiota were evaluated using 16S rRNA amplicon sequencing. To identify and confirm the mechanisms of D3, transcriptome analysis of ileum and molecular approaches on three animal models were performed. Results A significant body weight reduction was observed both in WT (12%) and GF (9%) mice treated with D3. D3 ameliorated leptin resistance and upregulated the expression of uroguanylin (UGN), which suppresses appetite via the UGN-GUCY2C endocrine axis. Similar effects were also found in diet-induced obese rat and macaque models. Furthermore, the abundance of intestinal Akkermansia muciniphila increased about 100 times through the IFNγ-Irgm1 axis after D3 treatment, which may further inhibit fat absorption by downregulating Cd36. Conclusion Our results indicated that D3 is a novel drug candidate for counteracting diet-induced obesity as a non-toxic and bioactive peptide. Targeting the UGN-GUCY2C endocrine axis may represent a therapeutic strategy for the treatment of obesity.
Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia
Authors: Rim Trad, Walid Warda, Vincent Alcazer, Mathieu Neto da Rocha, Ana Berceanu, Clémentine Nicod, Rafik Haderbache, Xavier Roussel, Yohan Desbrosses, Etienne Daguindau, Florain Renosi, Christophe Roumier, Lucie Bouquet, Sabeha Biichle, Melanie Guiot, Evan Seffar, Denis Caillot, Stephane Depil, Eric Robinet, Yahya Salma, Eric Deconinck, Marina Deschamps, Christophe Ferrand
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Acute myeloid leukemia (AML) remains a very difficult disease to cure due to the persistence of leukemic stem cells (LSCs), which are resistant to different lines of chemotherapy and are the basis of refractory/relapsed (R/R) disease in 80% of patients with AML not receiving allogeneic transplantation. Methods In this study, we showed that the interleukin-1 receptor accessory protein (IL-1RAP) protein is overexpressed on the cell surface of LSCs in all subtypes of AML and confirmed it as an interesting and promising target in AML compared with the most common potential AML targets, since it is not expressed by the normal hematopoietic stem cell. After establishing the proof of concept for the efficacy of chimeric antigen receptor (CAR) T-cells targeting IL-1RAP in chronic myeloid leukemia, we hypothesized that third-generation IL-1RAP CAR T-cells could eliminate AML LSCs, where the medical need is not covered. Results We first demonstrated that IL-1RAP CAR T-cells can be produced from AML T-cells at the time of diagnosis and at relapse. In vitro and in vivo, we showed the effectiveness of IL-1RAP CAR T-cells against AML cell lines expressing different levels of IL-1RAP and the cytotoxicity of autologous IL-1RAP CAR T-cells against primary cells from patients with AML at diagnosis or at relapse. In patient-derived relapsed AML xenograft models, we confirmed that IL-1RAP CAR T-cells are able to circulate in peripheral blood and to migrate in the bone marrow and spleen, are cytotoxic against primary AML cells and increased overall survival. Conclusion In conclusion, our preclinical results suggest that IL-1RAP CAR T-based adoptive therapy could be a promising strategy in AML treatment and it warrants the clinical investigation of this CAR T-cell therapy.
Beyond shame, sorrow, and apologies—action to address indigenous health inequities
Authors: Janet Smylie, Ricci Harris, Sarah-Jane Paine, Irma A Velásquez, None Nimatuj, Raymond Lovett
Journal: BMJ (2022)

<h3>ABSTRACT</h3> Chromosome segregation depends on a regulated connection between spindle microtubules and centromeric DNA. The kinetochore, a massive modular protein assembly, mediates this connection and also serves as a signaling hub that integrates and responds to changing cues during the cell cycle. Kinetochore functions evolve as the cell cycle progresses, culminating in the assurance of a persistent chromosome-microtubule connection during anaphase, when sister chromatids must transit into daughter cells uninterrupted. We previously determined the structure of the Ctf19 complex, a group of kinetochore proteins at the centromeric base of the kinetochore. We now present a high-resolution structure of a Ctf19 complex sub-assembly involved in centromere-microtubule contact: the Ctf3 complex bound to the Cnn1-Wip1 heterodimer. The resulting composite model of the Ctf19 complex and live-cell imaging experiments provide a mechanism for Cnn1-Wip1 recruitment to the kinetochore. The mechanism suggests feedback regulation of Ctf19 complex assembly and unanticipated similarities in kinetochore organization between yeast and vertebrates.
‘Warburg effect’ controls tumor growth, bacterial, viral infections and immunity – Genetic deconstruction and therapeutic perspectives
Authors: J. Pouysségur, I. Marchiq, S.K. Parks, J. Durivault, M. Ždralević, M. Vucetic
Journal: Seminars in Cancer Biology (2022)

The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e., MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumor microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumors (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumor growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
Effect of Physical Therapy vs Arthroscopic Partial Meniscectomy in People With Degenerative Meniscal Tears
Authors: Julia C. A. Noorduyn, Victor A. van de Graaf, Nienke W. Willigenburg, Gwendolyne G. M. Scholten-Peeters, Esther J. Kret, Rogier A. van Dijk, Rachelle Buchbinder, Gillian A. Hawker, Michel W. Coppieters, Rudolf W. Poolman
Journal: JAMA Network Open (2022)

<h3>Importance</h3> There is a paucity of high-quality evidence about the long-term effects (ie, 3-5 years and beyond) of arthroscopic partial meniscectomy vs exercise-based physical therapy for patients with degenerative meniscal tears. <h3>Objectives</h3> To compare the 5-year effectiveness of arthroscopic partial meniscectomy and exercise-based physical therapy on patient-reported knee function and progression of knee osteoarthritis in patients with a degenerative meniscal tear. <h3>Design, Setting, and Participants</h3> A noninferiority, multicenter randomized clinical trial was conducted in the orthopedic departments of 9 hospitals in the Netherlands. A total of 321 patients aged 45 to 70 years with a degenerative meniscal tear participated. Data collection took place between July 12, 2013, and December 4, 2020. <h3>Interventions</h3> Patients were randomly allocated to arthroscopic partial meniscectomy or 16 sessions of exercise-based physical therapy. <h3>Main Outcomes and Measures</h3> The primary outcome was patient-reported knee function (International Knee Documentation Committee Subjective Knee Form (range, 0 [worst] to 100 [best]) during 5 years of follow-up based on the intention-to-treat principle, with a noninferiority threshold of 11 points. The secondary outcome was progression in knee osteoarthritis shown on radiographic images in both treatment groups. <h3>Results</h3> Of 321 patients (mean [SD] age, 58 [6.6] years; 161 women [50.2%]), 278 patients (87.1%) completed the 5-year follow-up with a mean follow-up time of 61.8 months (range, 58.8-69.5 months). From baseline to 5-year follow-up, the mean (SD) improvement was 29.6 (18.7) points in the surgery group and 25.1 (17.8) points in the physical therapy group. The crude between-group difference was 3.5 points (95% CI, 0.7-6.3 points;<i>P</i> &lt; .001 for noninferiority). The 95% CI did not exceed the noninferiority threshold of 11 points. Comparable rates of progression of radiographic-demonstrated knee osteoarthritis were noted between both treatments. <h3>Conclusions and Relevance</h3> In this noninferiority randomized clinical trial after 5 years, exercise-based physical therapy remained noninferior to arthroscopic partial meniscectomy for patient-reported knee function. Physical therapy should therefore be the preferred treatment over surgery for degenerative meniscal tears. These results can assist in the development and updating of current guideline recommendations about treatment for patients with a degenerative meniscal tear. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01850719
Brain radiotoxicity-related 15CAcBRT gene expression signature predicts survival prognosis of glioblastoma patients
Authors: Jesús Reyes-González, Francisco Barajas-Olmos, Humberto García-Ortiz, Lorena Magraner-Pardo, Tirso Pons, Sergio Moreno, Lucinda Aguirre-Cruz, Andy Reyes-Abrahantes, Angélica Martínez-Hernández, Cecilia Contreras-Cubas, Jorge Barrios-Payan, Henry Ruiz-Garcia, Rogelio Hernandez-Pando, Alfredo Quiñones-Hinojosa, Lorena Orozco, María del Carmen Abrahantes-Pérez
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. Methods RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. Results We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. Conclusions 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.
The Prevalence and Determinants of NAFLD and MAFLD and Their Severity in the VA Primary Care Setting
Authors: Aaron P. Thrift, Theresa H. Nguyen, Codey Pham, Maya Balakrishnan, Fasiha Kanwal, Rohit Loomba, Hao T. Duong, David Ramsey, Hashem B. El-Serag
Journal: Clinical Gastroenterology and Hepatology (2022)
Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial
Authors: Fabrice Barlesi, Pascale Tomasini, Maryam Karimi, Stefan Michiels, Judith Raimbourg, Catherine Daniel, Henri Janicot, Anne Madroszyk, Clarisse Audigier-Valette, Elisabeth Quoix, Julien Mazieres, Denis Moro-Sibilot, Eric Dansin, Olivier Molinier, Hugues Morel, Eric Pichon, Alexis Cortot, Josiane Otto, François Chomy, Pierre-Jean Souquet, Nicolas Cloarec, Etienne Giroux-Leprieur, Ivan Bieche, Ludovic Lacroix, Sandrine Boyault, Valery Attignon, Isabelle Soubeyran, Alain Morel, Alicia Tran-Dien, Alexandra Jacquet, Filippo Gustavo Dall'Olio, Marta Jimenez, Jean-Charles Soria, Benjamin Besse
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 &amp;lt;1% (n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036). Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.
Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial
Authors: Thomas L. Holland, Adit A. Ginde, Roger Paredes, Thomas A. Murray, Nicole Engen, Greg Grandits, Andrew Vekstein, Noel Ivey, Ahmad Mourad, Uriel Sandkovsky, Robert L. Gottlieb, Mezgebe Berhe, Mamta K. Jain, Rubria Marines-Price, Barbine Tchamba Agbor Agbor, Lourdes Mateu, Sergio España-Cueto, Gemma Lladós, Eleftherios Mylonakis, Ralph Rogers, Fadi Shehadeh, Michael R. Filbin, Kathryn A. Hibbert, Kami Kim, Thanh Tran, Peter E. Morris, Evan P. Cassity, Barbara Trautner, Lavannya M. Pandit, Kirk U. Knowlton, Lindsay Leither, Michael A. Matthay, Angela J. Rogers, Wonder Drake, Beatrice Jones, Garyfallia Poulakou, Konstantinos N. Syrigos, Eduardo Fernández-Cruz, Marisa Di Natale, Eyad Almasri, Leire Balerdi-Sarasola, Sanjay R. Bhagani, Katherine L. Boyle, Jonathan D. Casey, Peter Chen, David J. Douin, D. Clark Files, Huldrych F. Günthard, R. Duncan Hite, Robert C. Hyzy, Akram Khan, Moses Kibirige, Robert Kidega, Ivan Kimuli, Francis Kiweewa, Jens-Ulrik Jensen, Bradley G. Leshnower, Joseph K. Lutaakome, Prasad Manian, Vidya Menon, Jose Luis Morales-Rull, D. Shane O'Mahony, J. Scott Overcash, Srikant Ramachandruni, Jay S. Steingrub, Hassan S. Taha, Michael Waters, Barnaby E. Young, Andrew N. Phillips, Daniel D. Murray, Tomas O. Jensen, Maria L. Padilla, David Sahner, Katy Shaw-Saliba, Robin L. Dewar, Marc Teitelbaum, Ven Natarajan, M. Tauseef Rehman, Sarah Pett, Fleur Hudson, Giota Touloumi, Samuel M. Brown, Wesley H. Self, Christina C. Chang, Adriana Sánchez, Amy C. Weintrob, Timothy Hatlen, Birgit Grund, Shweta Sharma, Cavan S. Reilly, Pedro Garbes, Mark T. Esser, Alison Templeton, Abdel G. Babiker, Victoria J. Davey, Annetine C. Gelijns, Elizabeth S. Higgs, Virginia Kan, Gail Matthews, B. Taylor Thompson, James D. Neaton, H. Clifford Lane, Jens D. Lundgren
Journal: The Lancet Respiratory Medicine (2022)
Cross-Modal Plasticity in Brains Deprived of Visual Input Before Vision
Authors: Guillermina López-Bendito, Mar Aníbal-Martínez, Francisco J. Martini
Journal: Annual Review of Neuroscience (2022)

Unimodal sensory loss leads to structural and functional changes in both deprived and nondeprived brain circuits. This process is broadly known as cross-modal plasticity. The evidence available indicates that cross-modal changes underlie the enhanced performances of the spared sensory modalities in deprived subjects. Sensory experience is a fundamental driver of cross-modal plasticity, yet there is evidence from early–visually deprived models supporting an additional role for experience-independent factors. These experience-independent factors are expected to act early in development and constrain neuronal plasticity at later stages. Here we review the cross-modal adaptations elicited by congenital or induced visual deprivation prior to vision. In most of these studies, cross-modal adaptations have been addressed at the structural and functional levels. Here, we also appraise recent data regarding behavioral performance in early–visually deprived models. However, further research is needed to explore how circuit reorganization affects their function and what brings about enhanced behavioral performance.
Rethinking Algorithm Performance Metrics for Artificial Intelligence in Diagnostic Medicine
Authors: Matthew A. Reyna, Elaine O. Nsoesie, Gari D. Clifford
Journal: JAMA (2022)

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PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
Authors: Jun-Cheng Wang, Dong-Ping Chen, Shi-Xun Lu, Jin-Bin Chen, Yuan Wei, Xue-Chao Liu, Yu-Hao Tang, Rongxin Zhang, Jian-Cong Chen, Anna Kan, Li Xu, Yao-Jun Zhang, Jiajie Hou, Dong-Ming Kuang, Min-Shan Chen, Zhong-Guo Zhou
Journal: Cancer Research (2022)

Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1β derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1β blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy.Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.